Fibrates are lipid regulating agents. Examples of fibrates include fenofibrate, bezafibrate, clofibrate and ciprofibrate. The compounds are regarded as prodrugs and are metabolised in vivo to their active metabolites. For illustrative purposes only, the following is based on a specific example of a fibrate, namely fenofibrate. Fenofibrate is chemically named as 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester. Fenofibrate is metabolised to the active substance fenofibric acid. Fenofibric acid has an elimination half-life of about 20 hours.
Fenofibric acid is the active metabolite of fenofibrate which leads to reduction in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides, and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increased high density lipoprotein (HDL) and apoproteins apo AI and apo AII. Fenofibrate acts as a potent lipid regulating agent offering unique and clinical advantages over existing products in the fibrate family of drug substances. Fenofibrate produces substantial reduction in plasma triglyceride levels in hypertriglyceridemic patients and in plasma cholesterol and LDL-C in hypercholesterolemic and mixed dyslipidemic patients. Clinical studies have demonstrated that elevated levels of total cholesterol, low density lipoprotein cholesterol (LDL-C), and apo-lipoprotein B (apo B) are associated with human atherosclerosis. Decreased levels of high density lipoprotein cholesterol (HDL-C) and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with the development of atherosclerosis. Fenofibrate is also effective in the treatment of Diabetes Type II and metabolic syndrome. Fenofibrate is also indicated as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipedemia).
Fibrates are drug substances known to be poorly and variably absorbed after oral administration. Normally fibrates are prescribed to be taken with food in order to increase the bioavailability. Fenofibrate is very poorly soluble in water, and the absorption of which in the digestive tract is limited. An increase in its solubility or in its rate of solubilization leads to better digestive absorption. Therefore a number of improvements have been made in an effort to improve the bioavailability and efficacy of currently approved fenofibrate dosage forms. Various approaches such as micronization of the fenofibrate, addition of a surfactant, and co-micronization of fenofibrate with a surfactant have been explored in order to increase the rate of solubilization of fenofibrate.
U.S. Pat. No. 5,145,684 discloses nanoparticles of drug substances including lipid regulating agents having non-crosslinked surface modifier.
U.S. Pat. Nos. 6,375,986; 6,969,529; 7,320,802; 7,276,249; 7,927,627; 6,592,903 and US patent applications 2004/0087656; 2008/0241070; 2008/0138424 and 2007/0264348 disclose nanoparticulate compositions of fenofibrate.
U.S. Pat. Nos. 6,277,405; 6,074,670; 6,652,881; 7,037,529; 7,041,319; 6,589,552; 6,531,158; 7,101,574 and 7,863,331 and US patent applications 2004/0057998; 2007/0071812; 2008/0248101; 2011/0159082; 2010/0112049 and 2009/0035379 describe micronized fenofibrate compositions.
U.S. Pat. Nos. 4,895,726; 5,880,148 and 7,189,412 describe composition wherein fenofibrate is co-micronized with the surface-active agents.
U.S. Pat. No. 7,658,944 discloses tablet composition of fenofibrate with PEG and Poloxamer. U.S. Pat. No. 7,976,869 discloses fenofibrate tablet and granules comprising micronized fenofibrate, polyvinylpyrrolidone, and pregelatinised starch.
U.S. Pat. No. 6,828,334 discloses inclusion complex of fenofibrate with cyclodextrins.
U.S. Pat. No. 6,027,747 discloses solid dispersion of fenofibrate.
US 2006/0222706 and US 2006/0222707 describe fenofibrate in intimate association with menthol and surfactant active agents which provides much enhanced bioavailability of fenofibrate.
U.S. Pat. No. 6,531,158 and US 2003/0138496 disclose composition of micronized fenofibrate with inert hydro soluble carriers.
WO 2010/082214 discloses a fenofibrate formulation with enhanced oral bioavailability comprising fenofibrate dissolved in a lipophilic surfactant. It also discloses that such formulation at lower doses may improve side effect profile.
US 2007/0014846 discloses compositions, particularly, pharmaceutical compositions in particulate form such as granulate or in solid dosage forms comprising a combination of a fibrate and a statin. More specifically, it discloses a solid pharmaceutical composition comprising atorvastatin and a low dose, i.e. a reduced amount, of fenofibrate having improved bioavailability and/or improved pharmacological response, i.e. improved effect.
US 2004/0057999 discloses an orally administrable fenofibrate tablet, wherein the required daily dose is lower than 200 mg.
Micronization of the drug and the addition of surface active agents have raised the bioavailability of fenofibrate thereby allowing the amount of drug dose to be reduced from 100 mg per dose to 67 mg per dose and then subsequently to 54 mg per dose, all with the same bioavailability in the fed state. Similarly the nanoparticle formulations of the drug have further allowed the reduction of the dose to 48 mg per dose with the bioavailability of the “fasted state” being reported as similar to the fed state. Further, the applicants have found that the composition comprising nanoparticulate fenofibrate at reduced doses imposes bioequivalence problems when compared with Antara® Capsule containing micronized fenofibrate under fasting condition.
The above disclosed prior arts direct various fenofibrate compositions wherein fenofibrate is present either in nanoparticle or in micronized form. None of the prior arts discloses the use of mixture of nanoparticulate fenofibrate and micronized fenofibrate that too for the reduced dose oral pharmaceutical composition of fenofibrate. The applicants surprisingly found that these compositions can be made bioequivalent to Antara® capsules under fasting condition by appropriate selection of the particle size of fenofibrate. The compositions of the invention are also substantially free of food effect.
Thus the present invention relates to a reduced dose oral pharmaceutical composition of fenofibrate comprising mixture of nanoparticulate fenofibrate and micronized fenofibrate which exhibits substantial bioequivalence to Antara® Capsules under fasting condition and is substantially free of food effect. Further, the reduced dose oral pharmaceutical composition of the present invention offers advantages such as (1) smaller doses of drug required to obtain the same pharmacological effect; (2) smaller tablet or capsule or other smaller solid dosage form in size (3) substantially similar pharmacokinetic profiles of fenofibrate composition when administered in the fed and the fasted state (4) reduction of side-effects associated with higher doses.